With nearly 29.5 million adults (18 years or older) in the United States with an alcohol use disorder (AUD) and an annual total economic cost of $249 billion, there is a clear need for more interventions to treat AUDs. More treatment options can help minimize the negative consequences felt by individuals with AUD, their families, workplaces, and society as a whole. One aspect of treatment, in addition to well-known methods, such as individual therapies and mutual-help groups, is the use of medications. Several medications are approved by the FDA for treating AUD, including naltrexone, acamprosate, and disulfiram. Other medications, such as topiramate, gabapentin, varenicline, baclofen, and prasozin have shown promise.

The drug development process, however, is extremely lengthy (approximately 18 years from discovery to market for CNS compounds) and very expensive. To help encourage the development of medications to treat AUD, and to bridge the gap between preclinical studies and Phase III clinical trials, NIAAA has a well-developed, integrated program called the NIAAA Alcohol Pharmacotherapy Evaluation Program (APEP). APEP efficiently advances candidate therapeutic compounds by conducting Phase II, human laboratory, and alcohol interaction clinical trials via three programs:

• NIAAA’s Clinical Investigations Group (NCIG)
• NIAAA’s Human Laboratory Program (HLAB)
• NIAAA’s Alcohol Interaction Program (ALC InX)

Candidate compounds that have demonstrated efficacy and safety in preclinical studies could be considered for testing in HLAB studies. The results of HLAB studies and/or other human laboratory studies could be the basis for advancing candidate drugs for further evaluation in NCIG Phase II clinical trials. For novel compounds alcohol interaction studies (ALC InX) are generally required for Phase I testing.

APEP trials are supported by a contract mechanism and designed by the NIAAA APEP team, in collaboration with the medication’s stakeholders, utilizing established paradigms and protocols. APEP trials are generally completed within 1-2 years and are conducted under Good Clinical Practice (GCP).

The NIAAA’s APEP team is composed NIAAA staff from the Medications Development Branch (MDB) within the Division of Treatment and Recovery (DTR) and the Office of the Director:

• Raye Z. Litten, Ph.D. (Project Officer)
• Daniel E. Falk, Ph.D. (Principal Investigator)
• Chamindi Seneviratne, M.D. (Principal Investigator)
• Megan Ryan, M.B.A. (Clinical Trials Operations and Technology Innovation Officer)
• Andrew Rodewald, M.A. (Health Science Policy Analyst)

For more information on APEP, contact:
Raye Z. Litten, Ph.D.
(301) 443-0636
rlitten@mail.nih.gov

NIAAA’s Clinical Investigations Group (NCIG)

Founded in 2007, NCIG was formed to test the safety and effectiveness of promising compounds in proof-of-concept Phase II clinical trials. NCIG encourages proposals from pharmaceutical companies with promising compounds for the treatment of AUD. The pharmaceutical industry’s response to the NCIG program has been positive. Numerous major pharmaceutical companies have contacted NIAAA with potential compounds for testing via the NCIG program, including AbbVie and Arbor Pharmaceuticals, with whom NCIG has completed clinical trials on new molecular entities. Additionally, NCIG hopes to serve as a model for pharmaceutical companies by improving clinical trial methodology to best detect a treatment’s effect with minimal cost and time.

When considering compounds to evaluate in the NCIG program, NIAAA looks for signs of efficacy shown in prior research, such as a reduction in drinking or craving for alcohol or other subjective effects. Candidate compounds include repurposed medications (i.e., those already marketed for the treatment of other diseases or disorders), as well as new compounds currently in development by pharmaceutical companies. When a compound shows signs of efficacy, NIAAA works collaboratively with the company to increase the likelihood that the drug will be made available to patients.

NCIG has successfully completed 5 Phase II, randomized, placebo-controlled multi-site clinical trials since the program’s inception in 2007 (most of these NCIG databases are available to researchers per request and approval):

• Quetiapine, an atypical antipsychotic medication used in treating psychiatric disorders, was examined in 224 very heavy-drinking alcohol-dependent individuals. Quetiapine significantly reduced depressive symptoms and improved sleep compared to placebo but had no significant effect on drinking outcomes ⁽¹⁾. ClinicalTrials.gov Identifier: NCT00498628. Quetiapine Study overview, database application, and instructions.

• Levetiracetam XR (Keppra XR®), an antiseizure drug, was tested in 130 very heavy-drinking alcohol dependent individuals. Levetiracetam XR decreased the number of alcohol-related consequences compared to placebo but had no significant effect on drinking or other outcomes ⁽²⁾. ClinicalTrials.gov Identifier: NCT00970814. Levetiracetam Study overview, database application, and instructions

• Varenicline (Chantix®), a smoking cessation medication, was evaluated in 200 alcohol-dependent individuals. Varenicline significantly reduced alcohol consumption and craving, making it a potentially viable option for the treatment of alcohol dependence ⁽³⁾. ClinicalTrials.gov Identifier: NCT01146613. Varenicline Study overview, database application, and instructions

• ABT-436, a novel arginine vasopressin (AVP) type 1B receptor (V1B) antagonist developed by the pharmaceutical company, AbbVie, was evaluated in 148 alcohol dependent individuals. ABT-436 significantly increased the percentage of days abstinent compared to placebo ⁽⁴⁾. ClinicalTrials.gov Identifier: NCT01613014

• Gabapentin enacarbil extended-release (HORIZANT®), a gabapentin prodrug formulation, was tested in 346 individuals with at least moderate alcohol use disorder. HORIZANT® had no effect on alcohol consumption, alcohol craving, alcohol-related consequences, sleep problems, smoking, and depression/anxiety symptoms ⁽⁵⁾. ClinicalTrials.gov Identifier: NCT02252536. HORIZANT® (Gabapentin Enacarbil) Extended-Release Study overview, database application, and instructions

• Oxytocin nasal spray is currently being evaluated in 100 individuals with at least moderate alcohol use disorder. ClinicalTrials.gov Identifier: NCT03878316.

References:

⁽¹⁾ Litten RZ, Fertig JB, Falk DE, et al. A double-blind, placebo-controlled trial to assess the efficacy of quetiapine fumarate XR in very heavy-drinking alcohol-dependent patients. Alcohol Clin Exp Res. 2012;36(3):406-416. doi:10.1111/j.1530-0277.2011.01649.x. PMID: 21950727
 ⁽²⁾ Fertig JB, Ryan ML, Falk DE, et al. A double-blind, placebo-controlled trial assessing the efficacy of levetiracetam extended-release in very heavy drinking alcohol-dependent patients. Alcohol Clin Exp Res. 2012;36(8):1421-1430. doi:10.1111/j.1530-0277.2011.01716.x. PMID: 22324516
 ⁽³⁾ Litten RZ, Ryan ML, Fertig JB, et al. A double-blind, placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence. J Addict Med. 2013;7(4):277-286. doi:10.1097/ADM.0b013e31829623f4. PMID: 23728065
⁽⁴⁾ Ryan ML, Falk DE, Fertig JB, et al. A Phase 2, Double-Blind, Placebo-Controlled Randomized Trial Assessing the Efficacy of ABT-436, a Novel V1b Receptor Antagonist, for Alcohol Dependence. Neuropsychopharmacology. 2017;42(5):1012-1023. doi:10.1038/npp.2016.214. PMID: 27658483
⁽⁵⁾ Falk DE, Ryan ML, Fertig JB, et al. Gabapentin Enacarbil Extended-Release for Alcohol Use Disorder: A Randomized, Double-Blind, Placebo-Controlled, Multisite Trial Assessing Efficacy and Safety. Alcohol Clin Exp Res. 2019;43(1):158-169. doi:10.1111/acer.13917. PMID: 30403402

Human Laboratory Program (HLAB)

The Human Laboratory Program (HLAB) serves to screen potential medications in human laboratory trials, prior to conducting more expensive Phase II clinical trials. HLAB is a network of high-quality laboratory sites capable of conducting multi-site, double-blind, randomized, controlled trials using established alcohol-related human laboratory paradigms to evaluate the efficacy and safety of therapeutic compounds for the treatment of AUD. HLAB trials conducted to date have used an alcohol cue-reactivity paradigm, which assesses whether a study medication reduces craving in response to alcohol cues. HLAB trials also investigate several secondary outcomes, including naturalistic drinking, mechanistic outcomes (e.g., mood, sleep, alcohol-related consequences), and safety outcomes.

HLAB Studies conducted to date:

• Varenicline (Chantix®), a nicotinic acetylcholine receptor (nAChR) partial agonist with high affinity for the α4β2 receptor that is FDA-approved as a smoking cessation medication, was evaluated in 48 alcohol-dependent individuals using an alcohol cue-elicited alcohol craving human laboratory paradigm. Varenicline did not attenuate cue-induced alcohol craving relative to placebo, but craving captured during the cue reactivity paradigm significantly predicted subsequent alcohol use in real-world settings during the clinical trial⁽¹⁾. ClinicalTrials.gov Identifier: NCT03035708.

• ANS-6637, a selective, reversible inhibitor of aldehyde dehydrogenase 2 (ALDH2) developed by Amygdala Neurosciences, was evaluated in 81 alcohol-dependent individuals using an alcohol cue-elicited alcohol craving human laboratory paradigm. This study yielded critical safety data about unexpected liver toxicity with ANS-6637, leading to early termination. However, preliminary data support the hypothesis that selective ALDH2 inhibition may reduce drinking, alcohol consequences and craving although effect sizes may be unreliable due to the small sample size. ClinicalTrials.gov Identifier: NCT03970109.

• ASP-8062, a novel compound with positive allosteric modulator (PAM) activity on the γ-aminobutyric acid type B (GABA_B) receptor that is currently being developed by Astellas Pharma Global Development (Astellas) for the treatment of opioid use disorder and AUD, was evaluated in 60 alcohol-dependent individuals using an alcohol cue-elicited alcohol craving human laboratory paradigm. Data analysis is underway. ClinicalTrials.gov Identifier: NCT05096117.

⁽¹⁾ Miranda R Jr, O'Malley SS, Treloar Padovano H, et al. Effects of Alcohol Cue Reactivity on Subsequent Treatment Outcomes Among Treatment-Seeking Individuals with Alcohol Use Disorder: A Multisite Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Varenicline. Alcohol Clin Exp Res. 2020;44(7):1431-1443. doi:10.1111/acer.14352. PMID: 32363592

Alcohol Interaction Program (ALC InX)

The Alcohol Interaction Program (ALC InX) is the newest addition to NIAAA’s APEP, serving to evaluate the safety and tolerability of combining candidate compounds with alcohol in humans as part of the FDA-required Phase I studies. ALC InX evaluations include physiological and subjective effects, pharmacodynamics, pharmacokinetics, and pharmacokinetic/pharmacodynamic relationships.